Evaluation of P2Y12 Inhibitor De-Escalation Regimens on Platelet Reactivity in High Bleeding Risk Patients with Acute Coronary Syndrome Post-Stenting

The primary objective of the study is to evaluate the **pharmacodynamic** effect of three different regimens of P2Y12 inhibitor de-escalation (prasugrel 5mg, ticagrelor 60mg/bid, or clopidogrel 75mg) compared to full-dose potent P2Y12 inhibitors (prasugrel 10mg or ticagrelor 90mg bid) on platelet reactivity. The study aims to determine which treatment achieves the highest proportion of patients in the optimal platelet reactivity (OPR) at treatment steady-state. This is clinically relevant as it may inform treatment strategies for patients with acute coronary syndrome, particularly those at high bleeding risk, by optimizing antiplatelet therapy to balance efficacy and safety.

Secondary objectives include:

• Evaluating the clinical impact of P2Y12 inhibitor de-escalation versus full-dose potent P2Y12 inhibition on major, minor, and nuisance bleeding according to the Bleeding Academic Research Consortium definition (BARC 1-5 bleeding) at 5 months after randomization.
• Assessing ischemic and net clinical events and quality of life in the four treatment arms.

The clinical trial involves participants diagnosed with **acute coronary syndrome**. The study population includes both male and female subjects, with an age range spanning from 18 to 64 years. Participants are generally in a stable health condition, having been treated with percutaneous coronary intervention (PCI) due to a recent acute coronary syndrome event, such as unstable angina or myocardial infarction, within the past 30 ±7 days. They are currently on dual antiplatelet therapy (DAPT) with full-dose potent P2Y12 inhibitors, in accordance with international guidelines. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Selection criteria include patients at high bleeding risk (HBR) as defined by standard criteria, such as PRECISE-DAPT ≥25 or HBR-ARC with specific criteria. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the pharmacodynamic effects of different **P2Y12 inhibitor** de-escalation regimens in patients with **acute coronary syndrome** who have undergone coronary stenting and are at high risk of bleeding. The trial employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. Participants will be randomly assigned to receive either a reduced dose of prasugrel, ticagrelor, or clopidogrel, or continue with a full-dose potent P2Y12 inhibitor regimen. The primary objective is to assess platelet reactivity and determine which treatment achieves the highest proportion of patients in the optimal platelet reactivity range at treatment steady-state.

The trial is expected to last until June 2026, with participant involvement spanning approximately six months. The sequence of study visits includes an initial screening visit to confirm eligibility based on criteria such as recent treatment with percutaneous coronary intervention (PCI) and dual antiplatelet therapy (DAPT). Following randomization, participants will attend follow-up visits at specified intervals to monitor platelet reactivity and assess any adverse clinical events. The primary endpoint will be measured 14±2 days after study inclusion, with additional assessments conducted at various time points to evaluate secondary endpoints, including bleeding incidence and platelet-derived thrombogenicity.

Participants may be withdrawn from the study if they experience significant adverse events, fail to adhere to the study protocol, or withdraw consent. The study will utilize the VerifyNow system to measure platelet reactivity units (PRU) and assess the incidence of optimal platelet reactivity. Secondary endpoints will include the incidence of bleeding events classified by the BARC definition, as well as the evaluation of high and low platelet reactivity proportions. The trial will also conduct a cost-effectiveness analysis and assess health mobility, mental scales, perceived stress, and non-adherence using validated scales.

The clinical trial involves the administration of several **experimental medications** to evaluate their effects on platelet reactivity and clinical outcomes in patients with recent acute coronary syndrome and high bleeding risk. **Ticagrelor** is one of the primary medications used in this study. It is administered in the form of a **film-coated tablet** and is taken orally. The maximum daily dose of ticagrelor is 180 mg, with a total dose not exceeding 180 mg per day. The treatment period for ticagrelor is up to 6 months. The study also includes a lower dose regimen of ticagrelor, administered as a 60 mg tablet twice daily (bid), to assess its pharmacodynamic effects compared to the full-dose regimen.

**Acetylsalicylic acid** is used as an auxiliary treatment in the trial. It is provided in the form of a **hard capsule** and is also administered orally. The maximum daily dose is 100 mg, with a total dose not exceeding 100 mg per day. The treatment duration for acetylsalicylic acid is up to 6 months. This medication serves as a standard-of-care therapy to complement the experimental treatments being evaluated.

Another experimental medication in the trial is **clopidogrel**, marketed as CLOPIDOGREL DOC Generici 75 mg film-coated tablets. Clopidogrel is administered orally, with a maximum daily dose of 75 mg and a total dose not exceeding 600 mg over the treatment period. The treatment duration for clopidogrel is up to 6 months. This medication is used to compare its effects on platelet reactivity with other P2Y12 inhibitors in the study.

**Prasugrel** is also included in the trial, available in two formulations: a generic version and a branded version, Prasugrel Mylan 10 mg film-coated tablets. Both formulations are administered orally. The generic prasugrel has a maximum daily dose of 60 mg, while the branded version has a maximum daily dose of 10 mg, with a total dose not exceeding 60 mg over the treatment period. The treatment duration for prasugrel is up to 6 months. The trial aims to evaluate the effects of prasugrel at different dosages on platelet reactivity and clinical outcomes.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the prescribed regimens. The trial's primary objective is to determine which treatment regimen achieves the highest proportion of patients in the optimal platelet reactivity range at treatment steady-state.

The efficacy of the clinical trial will be assessed primarily through the measurement of **platelet reactivity** using the VerifyNow system. The primary endpoint is the incidence of optimal platelet reactivity (OPR), defined as a platelet reactivity unit (PRU) between 85 and 208, measured 2 hours after drug maintenance dose (MD) at 14±2 days from study inclusion. This assessment will determine which treatment regimen achieves the highest proportion of patients in the OPR at treatment steady-state.

Secondary endpoints include the incidence of bleeding events categorized by the BARC definition, platelet reactivity at various timepoints, and the proportion of high and low platelet reactivity. These will be measured before the first randomized treatment administration, 2 hours after the first administration, and before and after MD at 14±2 days. Additional assessments include platelet-derived thrombogenicity, adverse clinical events up to 5 months post-randomization, and cost-effectiveness analysis. Tools such as health mobility and mental scales, perceived stress scales, and adherence scales will also be utilized to gather comprehensive efficacy data.